The liver is the largest organ in the human body, located in the superior portion of the right upper abdomen. This organ is highly complex and specialized and performs many crucial biochemical functions. The liver is critically involved in the removal of toxins from the body and in the manufacture of proteins including energy storage and blood clotting factors. The liver is also involved in storing minerals, vitamins and glucose in the form of glycogen, which is metabolized in large quantities to provide energy. The liver also plays a role in red blood cell metabolism and the break-down of certain metabolic byproducts in the blood stream.
Nonalcoholic steatohepatitis (NASH) is a liver disease that is frequently reported in both men and women, although it most often appears in women and is especially prevalent in the obese. Although the disease has been observed to be accompanied by several other pathological conditions, including diabetes mellitus, hyperlipidemia and hyperglycemia, the cause and progression of the disease, as well as the causal or temporal relation to these conditions, is not well understood. However, in patients suffering from NASH, certain characteristics of liver tissue and abnormalities of function are typical. Specifically, fatty deposits, tissue degeneration, inflammation, cell degeneration, cirrhosis, elevation of free fatty acids and other such abnormalities have come to be associated with nonalcoholic steatohepatitis and are frequently seen in patients suffering from NASH.
Steatohepatitis, excess fat in the liver, is a condition often observed in cases of starvation, overloading of carbohydrates, absence of energy in the form of proteins, obesity, and cortico steroid therapy. It has been hypothesized that the accumulation of fat in the liver may be the result of increased accumulation of free-fatty acids, increased manufacture of fatty acids in the liver, decreased oxidation of free fatty acids, or the synthesis or secretion of LDL cholesterol. The increased level of free fatty acids in some cases of steatohepatitis may implicate the reactivity of free fatty acids with biological membranes. NASH patients exhibit increased asparate aminotransferase and/or alanine aminotransferase activity, characteristically at least 150% of normal. To confirm the clinical diagnosis of NASH, evidence of zero to low alcohol consumption is required and confirmation of the absence of a previous infection with hepatitis B virus or hepatitis C. The specific diagnosis of nonalcoholic steatohepatitis may also depend on detailed analysis of liver biopsy specimens. The histological features identified may include macrovesicular fat, cirrhosis, inflammation of the parenchyma and the presence of Mallory hyaline bodies.
Approximately 8% of patients who undergo liver biopsies will show histological evidence of NASH. The physiological condition that most commonly accompanies NASH is obesity, with approximately 70% and above of NASH sufferers also displaying clinically diagnosed obesity. NASH is particularly prevalent in obese patients who have undergone jejunal bypass to treat the obesity. In NASH patients, the extent of obesity tends to be generally correlated with the amount of steatosis and to be unrelated to non-insulin-dependent diabetes mellitis. However, non-insulin-dependent diabetes mellitis increases the prevalence of steatohepatitis especially in patients requiring insulin. Weight loss in patients before death does not appear to alleviate the steatosis and, somewhat paradoxically, obese patients who lost weight before death may actually have a higher incidence of steatohepatitis. The disease rarely occurs in any patient under the age of 30, but is particularly prevalent in patients in their 50s and 60s.
Even in NASH patients who do not consume any alcohol at all, liver biopsy specimens tend to mimic those seen in patients suffering from alcoholic hepatitis. However, a comparison of the two conditions reveals a higher incidence of vacuolation (indicative of diabetes) and steatosis in NASH as compared to alcoholic hepatitis. Patients suffering from alcoholic hepatitis also have a higher incidence of periportal and pericellular fibrosis and proliferation of the bioduct. Overall, the symptoms and histological damage observed in alcoholic hepatitis patients are more severe than in NASH.
Many experimental studies have been conducted to better understand NASH. For example, Susumu Itoh et al. studied 16 nonalcoholic steatohepatitis patients and 22 alcoholic hepatitis patients and discovered various differences between these two similar liver diseases. Susumu Itoh et al., Comparison between Nonalcoholic Steatohepatitis and Alcoholic Hepatitis, 82 The American Journal of Gastroenterology 650 (July 1987). Other examples include Ian R. Wanless & John S. Lentz, Fatty Liver Hepatitis (Steatohepatitis) and Obesity: An Autopsy Study with Analysis of Risk Factors, 12 Hepatology 5:1106 (1990)(concluding that fatty acids have a role in the hepatocellular necrosis found in some obese individuals) and Bruce R. Bacon et al., Nonalcoholic Steatohepatitis: An Expanded Clinical Entity, 107 Gastroenterology 1103 (1994)(concluding that NASH should not only be considered as a disease predominantly seen in obese women with diabetes).
Choline deficiency has been known to cause fatty infiltration of the liver in animals such as rats, hamsters, pigs and dogs. Thus, a deficiency in choline may result in the inability of the liver to transport fatty acids such as triglycerides. Indeed, one recent study has shown that hepatic steatosis in many long-term total parenteral nutrition patients may be caused by a deficiency in plasma-free choline, and that such deficiency may be reversed with lecithin (phosphatidylcholine) supplementation. Alan Buchman et al., Lecithin Increases Plasma Free Choline and Decreases Hepatic Steatosis in Long-Term Total Parenteral Nutrition Patients, 102 Gastroenterology 1363 (1992).
Although nonalcoholic steatohepatitis is generally viewed as a progressive liver disease, the condition tends to be stable over at least a few years in patients exhibiting the most common clinical manifestations of the disease. A majority of patients who have undergone repeated biopsies over a multi-year period have, for the most part, revealed no significant morphological changes over this period. To date, scientists have not discovered any biochemical, clinical or histological measurements that can distinguish between patients that will suffer comparatively stable NASH with those for whom NASH is a precursor to a more serious liver ailment, and even death.
Currently, an established therapy for patients suffering from NASH does not exist. Weight loss is a common prescription, simply because obesity is frequently found in patients suffering from NASH. The effect of a reduction in weight loss on NASH cannot be determined with certainty, however, because obese patients seldom maintain significant weight reduction.